PROJECT SUMMARY EPIPROTEOME OF SEZARY SYNDROME Peripheral T-cell lymphomas including cutaneous T-cell lymphomas (CTCL) are poorly understood and many subtypes exhibit aggressive clinical course and high mortality with short (2-year) life expectancy after diagnosis. Poor understanding of mechanisms underlying the pathogenesis of CTCLs contributes to suboptimal diagnostic subcategorization and lack of targeted therapies. Mycosis fungoides (MF) and Szary syndrome (SS) are two major forms of CTCL. Clinical staging and outcome of MF and SS is dependent on the quantity of neoplastic cells in the blood. While SS is an aggressive disease with poor overall survival (42.3% at 5 years and is by definition diagnosed at late stage disease, there are many patients with low tumor burden (Early-stage CTCL) who suffer from delay in diagnosis due to the subjective nature of the diagnostic criteria. The mean diagnostic delay (measured as the time from emergence of skin lesions to the diagnosis of SS) is long (4.2 year; median 2.8 years) with a significant variation (1 month to 32 years). The suboptimal diagnostic accuracy and imprecision of disease detection necessitates the development of qualitative and objective biomarkers of SS. Histone deacetylase inhibitors (HDACi) have been introduced as anti- cancer agents which achieve their therapeutic effect in part by inhibiting deacetylation of histones. However, despite the fact that CTCLs including SS were the first diseases which received FDA approval for treatment with HDACi, responses to the drugs in each patient are markedly variable. An unmet clinical need is the absence of reliable biomarkers directly interrogating the histone PTMs that can predict response to the drugs. We recently developed a novel mass spectrometry (MS)-based strategy for unbiased identification of histone PTMs and demonstrated its applicability for the analysis of primary samples of SS. Importantly, these epiproteomic profiling studies reveal distinctive histone PTM marks that distinguish SS from CD4+ T-cells from healthy individuals. It is our central hypothesis that epiproteomic modifications (the histone code) of SS can be utilized for the early diagnosis and as predictors of response to HDACi. Accordingly, we propose to investigate the utility of MS-based epiproteomic profiling for the early diagnosis of SS and for the prediction of response to HDACi. The overall impact of this proposal is the establishment of novel epiproteomic biomarkers that will improve outcomes particularly in aggressive CTCLs.